[7] At age 17, in 1992, Henderson starred as Stuart Neilson in the New Zealand prime-time soap opera Shortland Street.

[9] He subsequently lived in Australia for three years[10] and appeared in a number of Australian films and television productions including Echo Point and Home and Away.

Henderson moved to the United States in 1997 to pursue a career in Hollywood films and to train in a two-year program at the Neighborhood Playhouse in New York City with a student visa.

[17] Later that year, he starred opposite Aishwarya Rai in the British romantic film Bride and Prejudice and appeared in Britney Spears' "Toxic" music video.

[6] In 2006, Henderson received rave reviews in London's West End in a theatre production of Fool for Love with Juliette Lewis.

In 2010, Henderson was cast in Grey's Anatomy creator Shonda Rhimes' short-lived television series Off the Map as a New Zealand doctor.

Henderson told Deadline that his departure was a storytelling-based decision, adding, "This [was] my final year so I was expecting Nathan’s storyline to be wrapped up.

[24] Since 2019, Henderson has co-starred on the Netflix series Virgin River alongside Alexandra Breckenridge, playing the role of Jack Sheridan, a former marine with PTSD.